Peptides and proteins play critical roles in the regulation of biological processes. Peptides, for example, play a regulatory role as hormones and inhibitors, and are also involved in immunological recognition. The significant biological role of peptides makes it important to understand their interactions with the receptors to which they bind.
The determination of the receptor-bound conformation of a peptide is invaluable for the rational design of peptide analogs. Because peptides are highly flexible molecules, the structures of which are strongly influenced by the environment in which they reside, the peptides themselves are generally not useful for determining their receptor-bound conformation. Therefore, it is necessary to perform structure-function studies in a systematic way to provide information about the specific amino acid residues and functional groups in peptides that are important to biological activity. Studies of this nature can utilize conformationally constrained peptide mimetics. For example, Hruby, Trends Pharmacol. Sci., 8:336-339 (1987) suggests that conformational constraints can provide information about the different requirements that a receptor has for a ligand to be an agonist or antagonist.
Peptide mimetics or peptidomimetics are structures which serve as appropriate substitutes for peptides and/or amino acids in interactions with receptors and enzymes. The development of rational approaches for discovering peptide mimetics is a major goal of medicinal chemistry. Such development has been attempted both by empirical screening approaches and specific synthetic design. Specific design of peptide mimetics has utilized peptide backbone modifications, chemical mimics of peptide secondary structures and covalent constraints on the peptide parent to facilitate such peptide secondary structures.
Alpha helices present the side chains of the residues thereof along a rod-like helical structure. Approximately 3.6 amino acid residues make up a single turn of an alpha-helix. Thus, side chains that are adjacent in space form a “side” of an alpha-helix with residues which occur every three to four residues along the linear amino acid sequence. As customary in the art, this spacing can be referred to as “i, i+3/i+4, i+7” and the like to indicate that the side chains of residues offset from residue “i” lie approximately along a side of the alpha helix, in spatial proximity. The term “face” in the context of alpha helices is synonymous with the term “side.” It is believed that the i, i+3/i+4 and i+7 residues can make crucial contacts with a target protein, and that such contacts constitute the majority of binding energy. Fairlie et al., Curr. Med. Chem., 5:29 (1998). The alpha-helix conformation is stabilized by steric interactions along the backbone as well as hydrogen bonding interactions between the backbone amide carbonyls and NH groups of each amino acid. The side chains of an alpha helix project with well known distances and angular relationships. Jain et al., Mol. Divers., 8:89-100 (2004).
The syntheses of peptidomimetics having a stabilized alpha-helical conformation have been achieved by introducing synthetic templates into the peptidic, by using β-hairpin mimetics, by using β-peptide sequences, and by using unnatural oligomers with discrete folding propensities. Small synthetic molecules able to mimic the surfaces of constrained peptides offer the advantage of improved stability, lower molecular weight and in some cases better bioavailability. Synthetic small molecules that adopt various well-defined secondary structures are well-documented in the art. A variety of strategies to enhance the propensity for alpha helix formation in peptides are known in the art. Exemplary methods include side-chain constraints, capping, and nonnatural amino acid substitutions.
Another class of constraints for alpha helices employ ring closing metathesis (RCM) reactions to form side chain to side chain bridges which incorporate a double bond (e.g., alkenylenyl bridges) or no double bond (e.g., alkylenyl bridges). The discovery of the olefin metathesis reaction provided a convenient path for synthesis and cleavage of carbon-carbon bonds under mild conditions. In particular, the use of RCM reactions catalyzed by ruthenium complexes has become a popular method for the formation of alkenylenyl bridged structures in organic syntheses. Application of this method to amino acids bearing unsaturated side chains (e.g., allylglycine, homoallylglycine and the like) and located in strategic positions of the peptide motif allows the preparation of cyclic peptides by solid-phase peptide synthetsis (SPPS) methods.
There is a need in the art for new GLP-1 receptor agonist compounds that have good stability, resistance to degradation, and good glucagon-like peptide-1 (GLP-1) receptor binding activity and in vivo glucose lowering activity and that are useful for treating diabetes and reducing body weight. To solve these needs, the disclosure herein provides, among other things, GLP-1 receptor agonist compounds having stabilized alpha-helical regions.